System for effecting smoke cessation

ABSTRACT

A system is disclosed which makes it possible for a patient to be delivered gradually reduced amounts of nicotine over time thereby allowing the patient to be gradually weaned off of dependence on nicotine and quit smoking. The system is comprised of a means for aerosolizing a formulation and containers of formulation. The formulation is comprised of nicotine in a pharmaceutically acceptable carrier. Preferably, a plurality of containers are produced wherein the concentration of nicotine in the different containers or different groups of containers is reduced. The patient uses containers with the highest concentration initially and gradually moves towards using containers with lower and lower concentrations of nicotine until the patient&#39;s dependence on nicotine is eliminated.

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/144,140, filed Jul. 16, 1999, which application isincorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates generally to a method for treatingconditions responsive to nicotine therapy. More specifically, theinvention relates to pulmonary administration of nicotine to effectsmoking cessation.

BACKGROUND OF THE INVENTION

[0003] Diseases related to cigarette smoking, such as lung disease,heart disease and cancer, claim an estimated 400,000 lives each year.The combustion of tobacco produces poisons and carcinogens that presenta significant health hazard for smokers and non-smokers alike. Nicotineis a principal component of tobacco, and the most pharmacologicallyactive. It is physically addictive, making it extremely difficult for asmoker to quit.

[0004] Smoking a cigarette delivers nicotine vapors to the lungs, wherenicotine is rapidly absorbed through the arteries and delivered to thebrain. Nicotine interacts with nicotinic cholinergic receptors in thebrain to induce the release of neurotransmitters and produce animmediate reward—the “rush” that smokers experience—that is associatedwith a rapid rise in blood level. A persistent stimulus is alsoproduced, and is associated with a high blood level of nicotine. Complexbehavioral and social aspects of smoking, e.g., the hand-to-mouthritual, etc., are also habit-forming.

[0005] A therapeutic approach to aid in smoking cessation is to providethe smoker with nicotine from sources other than cigarettes. A number ofnicotine replacement therapies have been developed to accomplish thisresult. Commercially available therapies deliver nicotine to thesystemic circulation via absorption through mucosal membranes or theskin. These include nicotine-containing chewing gum, sachets,transdermal patches, capsules, tablets, lozenges, nasal sprays and oralinhalation devices.

[0006] Nicotine delivery via inhalation offers the benefit of addressingthe psychological component of cigarette smoking in addition to thephysiological dependence on nicotine. Nicotine inhalation systemsrelease nicotine as a vapor (see U.S. Pat. Nos. 5,167,242; 5,400,808;5,501,236; 4,800,903; 4,284,089; 4,917,120; 4,793,366), aerosol (seeU.S. Pat. Nos. 5,894,841; 5,834,011) or dry powder (see U.S. Pat. No.5,746,227) when air is inhaled through the inhaler. A droplet ejectiondevice (U.S. Pat. No. 5,894,841) has also been described that delivers acontrolled dose of nicotine via inhalation. These systems deliver lowdoses of nicotine to the mouth and throat, where nicotine is absorbedthrough the mucosal membranes into the circulation. Some inhalationtherapies feature devices that simulate or approximate the look, feeland taste of cigarettes.

[0007] Currently available nicotine replacement therapies, such astransdermal and buccal systems, provide a low, steady-state blood levelof nicotine to the patient. The need remains for an smoking cessationtherapy that delivers a precise dose of nicotine to the lungs in aprofile that mimics the blood levels achieved by cigarettesmoking—providing an initial sharp rise in blood level followed by aslow release of nicotine—making it possible for the user to be weanedoff of nicotine and to quit smoking.

SUMMARY OF THE INVENTION

[0008] A system for aiding a patient in quitting smoking is disclosed.The system is comprised of a means for the delivery of aerosolizednicotine which makes it possible to gradually decrease the amount ofnicotine that the patient receives. The system comprises a means foraerosolizing a formulation comprised of nicotine and a means fordecreasing the amount of nicotine formulation which is aerosolizedand/or the amount which actually reaches the patient's circulatorysystem. The amount of nicotine aerosolized or effectively delivered tothe patient can be changed in several different ways using either thedevice aerosolization mechanism, the formulation or formulationcontainers loaded into the device.

[0009] A preferred system of the invention aerosolizes the liquidformulation by applying force to a container of nicotine formulation andcausing the nicotine formulation to be moved through a porous membranewhich results in creating particles of nicotine formulation which areinhaled by the patient. This system modifies the amount of nicotineaerosolized by providing a plurality of different containers ordifferent groups of containers wherein the different containers orgroups of containers contain different concentrations of nicotine. Apatient using the system can utilize packets of nicotine formulationcontaining a high concentration initially and then gradually switchtowards lower and lower concentrations so that the patient receivesessentially the same amount of aerosolized formulation but receivesgradually reduced amounts of nicotine due to the reduced concentrationof the nicotine in the formulation.

[0010] The same procedure described above can also be carried with a drypowder inhaler (DPI). Using the dry powder inhaler technology thepackets of dry powder nicotine formulation loaded into the device caninitially contain a relatively high concentration of nicotine.Thereafter, the concentration of nicotine in the dry powder formulationadded into the device is gradually decreased. Thus, using this systemthe same amount of dry powder is aerosolized, but the amount of nicotineis gradually decreased by decreasing the concentration or simply thetotal amount of nicotine in the dry powder package loaded into thedevice. The same procedure can be utilized with a conventional metereddose inhaler (MDI) device. It is somewhat more difficult to utilize theinvention with an MDI device. However, small pressurized canistersconventionally used with MDIs can contain different concentrations ofnicotine along with the propellant. By using a first container whichincludes the highest concentration of nicotine and gradually changing tolower and lower concentrations of nicotine in the pressurized canisterthe desired result of reducing the amount of nicotine delivered to thepatient can be obtained. The same results could be obtained by graduallydecreasing the amount of formulation released when the value of acontainer is opened.

[0011] When using a dry power inhaler or a system which aerosolizes aliquid formulation by moving the formulation through a porous membraneit is possible to decrease the amount of nicotine gradually by makingchanges in the device, or more specifically the operation of the device.For example, a dry powder inhaler often utilizes a burst of air in orderto aerosolize the dry powder. The burst of air could be decreased sothat not all of the powder is fully aerosolized or so that the powder isnot aerosolized in a completely efficient manner. In a more preferredembodiment the system for aerosolizing liquid formulation is adjusted atdifferent points so that different amount of pressure are applied to theformulation making it possible to aerosolize decreasing amounts offormulation and allowing the patient to be gradually weaned off ofnicotine.

[0012] The most preferred embodiment of the invention involves the useof a system which aerosolizes liquid formulations of nicotine containedwithin individual packets which packets include a porous membrane. Asindicated above the amount of nicotine that can be changed by changingthe amount of or concentration of nicotine in the packets. However, itis also possible to decrease the amount of nicotine actually deliveredto the patient's circulatory system by changing the size of the pores inthe membrane. When the pore size is in a preferred range then arelatively high concentration of the formulation aerosolized will reachthe patient's lungs and move from the lungs into the patient'scirculatory system. However, by making the pores larger the aerosolizedparticles created also become larger. The larger particles will not moveinto the lungs as efficiently as the smaller particles. Further, thelarger particles may be deposited in areas where they are not readilyabsorbed into the patient's circulatory system. Thus, in accordance witha preferred embodiment of the invention a plurality of differentcontainers are produced. The containers are different from each other inthat they contain different amounts or concentrations of nicotine.Alternatively, the containers are different from each other in that theyhave different porous membranes on them which make it possible toaerosolize the formulation in a somewhat less efficient manner overtime. It is possible to combine both or all three features together.More specifically, it is possible to produce containers which contain(1) smaller concentrations of nicotine; (2) smaller amounts of nicotine;or (3) have porous membranes which have different size or amounts ofpores so as to less efficiently aerosolize the formulation present inthe container.

[0013] A method for aiding in smoking cessation and for treatingconditions responsive to nicotine therapy by the administration ofnicotine is disclosed. A formulation comprised of nicotine isaerosolized. The aerosol is inhaled into the lungs of the patient. Onceinhaled, particles of nicotine deposit on lung tissue and from thereenter the patient's circulatory system. Because delivery is to thelungs, the patient's serum nicotine level is quickly raised to a desiredlevel—as quickly as if the user were smoking. The methods of theinvention produce arterial concentrations of nicotine similar tocigarette smoking.

[0014] Subsequently, the patient's dependence on nicotine is reduced bygradually reducing the dose of nicotine. The dose of nicotine is reducedby progressively increasing the size distribution of the aerosolizednicotine particles delivered to the patient. This decreases the amountof nicotine delivered to the patient's lungs, with the result thatnicotine absorption is less immediate and the blood plasma level islower.

[0015] A method of treatment is disclosed, comprising:

[0016] (a) aerosolizing a formulation comprised of nicotine creatingaerosolized particles which are sufficiently small as to enter thealveolar ducts;

[0017] (b) allowing a patient to inhale the aerosolized particles of (a)thereby causing nicotine to enter the patient's blood at air/blooddiffusion membranes;

[0018] (c) repeating (a) and (b) a plurality of times;

[0019] (d) aerosolizing a formulation comprised of nicotine creatingaerosolized particles which are too large to enter alveolar ducts butsufficiently small to enter primary and secondary bronchioles;

[0020] (e) allowing the patient to inhale the aerosolized particles of(d) into primary and secondary bronchioles; and

[0021] (f) repeating (d) and (e) a plurality of times.

[0022] The method is preferably further comprised of:

[0023] (g) aerosolizing a formulation comprised of nicotine creatingaerosolized particles which are too large to enter primary and secondarybronchioles but sufficiently small to enter the small bronchi;

[0024] (h) allowing the patient to inhale the aerosolized particles of(g) into small bronchi; and

[0025] (i) repeating (g) and (h) a plurality of times.

[0026] An aspect of the invention is a method of treatment wherebynicotine or a nicotine substitute is aerosolized, inhaled into areas ofthe respiratory tract including the lungs and provided to thecirculatory system of the patient at levels sufficient to simulatecigarette smoking.

[0027] An advantage of the invention is that the nicotine levels areraised almost immediately on administration.

[0028] Another advantage of the invention is that the patient cangradually be weaned off of the immediate effect of nicotine obtained viasmoking and gradually weaned off of the need of nicotine by,respectively, increasing particle size and decreasing dose size orconcentration.

[0029] A feature of the invention is that aerosolized particles ofnicotine having a diameter of about 0.5 to 8 microns (μ) are created andinhaled deeply into the lungs, thereby enhancing the speed andefficiency of administration.

[0030] It is an object of this invention to describe the utility ofdelivering nicotine by inhalation as a means of treating conditionsresponsive to nicotine therapy, and particularly for smoking cessationtherapy.

[0031] It is another object of this invention to describe the utility ofvarying the distribution of aerosolized particles of nicotine inhaled asa means of treating smokers wishing to quit.

[0032] It is another object of this invention to describe liquidformulations (which includes suspensions) of nicotine and derivativesthereof appropriate for pulmonary delivery.

[0033] It is another object of this invention to describe how nicotinedelivered via the lung can quickly increase blood plasma levels.

[0034] An aspect of the invention is a method whereby larger and largerparticles of aerosolized nicotine are administered to a patient overtime in order to first wean a smoking patient off of the addiction toimmediate nicotine and thereafter reduce the amount of nicotine in orderto wean the patient completely off of the addiction to nicotine, therebyallowing the patient to quit smoking.

[0035] A feature of this invention is that it allows for the formationof nicotine particles in different sizes designed for delivery todifferent areas of a patient's lungs.

[0036] An advantage of the invention is that it allows the patient to beweaned off of (1) the need for immediate nicotine delivery as obtainedwhen smoking, and (2) the need for nicotine at all.

[0037] These and other aspects, objects, advantages, and features of theinvention will become apparent to those skilled in the art upon readingthis disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038]FIG. 1 is a schematic view of a human lung branching pattern.

[0039]FIG. 2 is a schematic view of a human respiratory tract.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Before the devices, formulations, and methodology of the presentinvention are described, it is to be understood that this invention isnot limited to the particular device, components, formulations andmethodology described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is with the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention which will be limited only by theappended claims.

[0041] It must be noted that as used herein and in the appended claims,the singular forms “a,” “and,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a formulation” includes mixtures of different formulations andreference to “the method of treatment” includes reference to equivalentsteps and methods known to those skilled in the art, and so forth.

[0042] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, the preferred methodsand materials are now described. All publications mentioned herein areincorporated herein by reference to describe and disclose specificinformation for which the reference was cited in connection with.

Definitions

[0043] The term “nicotine” is intended to mean the naturally occurringalkaloid known as nicotine, having the chemical nameS-3-(1-methyl-2-pyrrolidinyl)pyridine, which may be isolated andpurified from nature or synthetically produced in any manner. This termis also intended to encompass the commonly occurring salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorate and pamoate salts. Nicotine is a colorless to paleyellow, strongly alkaline, oily, volatile, hygroscopic liquid having amolecular weight of 162.23 and the formula:

[0044] Structure and ionisation of nicotine. Nicotine is approximately10% of the particulate weight in cigarette smoke. Brand differenceschange this percentage. It is monoprotonated at most physiological pHvalues. The diprotonated ion would exist at pH values found in thestomach. Metabolism is largely due to oxidation. Cotinine is a majormetabolite; however, there are at least 4 primary metabolites ofnicotine and all are encompassed by the use of this term herein.

[0045] The term “nicotine” further includes any pharmacologicallyacceptable derivative, metabolite or analog of nicotine which exhibitspharmacotherapeutic properties similar to nicotine. Such derivatives andmetabolites are known in the art, and include cotinine, norcotinine,nornicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and5-hydroxycotinine or pharmaceutically acceptable salts thereof A numberof useful derivatives of nicotine are disclosed within the Physician'sDesk Reference (most recent edition) as well as Harrison's Principles ofInternal Medicine. In addition, applicants refer to U.S. Pat. Nos.5,776,957; 4,965,074; 5,278,176; 5,276,043; 5,227,391; 5,214,060;.5,242,934; 5,223,497; 5,278,045; 5,232,933; 5,138,062; 4,966,916;4,442,292; 4,321,387; 5,069,094; 5,721,257; all of which areincorporated herein by reference to disclose and describe nicotinederivatives and formulations.

[0046] The physiologically active form of nicotine is the S-(-)-isomer.Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis and trans isomers, R and Senantiomers, diastereomers, the racemic mixtures thereof, and othermixtures thereof, as falling within the scope of the invention.Additional asymmetric carbon atoms may be present in a substituent suchas an alkyl group. All such isomers, as well as mixtures thereof, areintended to be included in this invention.

[0047] The term “upper airways” and the like are used interchangeablyherein to define an area of the respiratory system which includes theoropharyngeal region and trachea. This area is the first area which airenters upon inhalation (see FIG. 1).

[0048] The terms “central airways,” “bronchial airways” and the like areused interchangeably herein to refer to a region of the respiratorysystem that includes generations 1 through 16 of the airways (seeFIG. 1) which removes particles larger than 3 μ in diameter. They arethe conductive airways that also clean particles from the lung using amucosal clearance mechanism. Upon inhalation, air passes through theupper airways into the central airways.

[0049] The terms “pulmonary region,” “peripheral region” and the likeare used interchangeably herein to define a region of the respiratorysystem where gas exchange occurs between the lungs and the circulatorysystem, i.e., where oxygen enters the blood and carbon dioxide leavesthe blood. The peripheral region includes generations 17 through 23 ofthe airways (see FIG. 1). Drugs delivered to this area generally have asystemic effect.

[0050] The terms “alveolar ducts,” “alveoli” and the like refer tocomponents in the pulmonary region of the lung which are approximately 3μ in diameter where gas exchange occurs between the air in the lungs andthe circulatory system.

[0051] The term “diameter” is used herein to refer to particle size asgiven in the “aerodynamic” size of the particle. The aerodynamicdiameter is a measurement of a particle of unit density that has thesame terminal sedimentation velocity in air under normal atmosphericconditions as the particle in question. This is pointed out in that itis difficult to accurately measure the diameter of small particles usingcurrent technology and the shape of such small particles may becontinually changing. Thus, the diameter of one particle of material ofa given density will be said to have the same diameter as anotherparticle of the same material if the two particles have the sameterminal sedimentation velocity in air under the same conditions. Inconnection with the present invention, it is important that particles,on average, have the desired diameter so that the particles can beinhaled and targeted to a specific area of the lungs. It is alsoimportant not to have particles which are too small in that suchparticles would be inhaled into the lungs and then exhaled withoutdepositing on the lung tissue in the same manner that particles of smokecan be inhaled and exhaled with only a small amount of the particlesbeing deposited on the lung tissue. An acceptable range for particlediameter varies depending on the area of the respiratory tract beingtargeted. To target the alveolar ducts and alveoli the particles shouldhave a diameter in a range of about 0.5 μ to about 2 μ. To target thearea above the alveolar ducts and below the small bronchi the diametershould be in the range of from about 2 μ to about 4 μ, and to target thesmall bronchi and above the particles should have a diameter of fromabout 4 μ to about 8 μ.

[0052] The term “porous membrane” shall be interpreted to mean amembrane of material in the shape of a sheet having any given outerperimeter shape, but preferably covering a package opening which is inthe form of an elongated rectangle, wherein the sheet has a plurality ofopenings therein, which openings may be placed in a regular or irregularpattern, and which openings have a diameter in the range of 0.25 μ to 4μ and a pore density in the range of 1×10⁴ to about 1×10⁸ pores persquare centimeter. Alternatively, the porous membrane may be merely anarea of the package which has pores therein wherein the pores have asize and a density as described above. The configuration and arrangementof the pore density may be changed so as to provide pores which arecapable of creating the desired amount of aerosol. For example, theporous membrane or area of the container may have some 10 to 10,000pores therein which pores are positioned in an area of from about 1 mm²to about 1 Cm². The membrane is preferably comprised of a materialhaving a density in the range of 0.25 to 3.0 mg/Cm², more preferably 1.7mg/Cm², and a thickness of about 2 μ to 20 μ, more preferably about 8 μto 12 μ. The membrane material is preferably hydrophobic and includesmaterials such as polycarbonates and polyesters which may have the poresformed therein by any suitable method including anisotropic etching orby etching through a thin film of metal or other suitable material.Pores can be created in the membrane which may be an area of thecontainer by use of techniques such as etching, plating or laserdrilling. The membrane materials may have pores with a conicalconfiguration and have sufficient structural integrity so that it ismaintained intact (will not rupture) when subjected to force in theamount of about 20 to 200 psi while the formulation is forced throughthe pores. The membrane functions to form an aerosolized mist when theformulation is forced through it. Those skilled in the art maycontemplate other materials which achieve this function as suchmaterials are intended to be encompassed by this invention.

[0053] The terms “treatment,” “treating,” and the like are usedinterchangeably herein to generally mean obtaining a desiredpharmacological and/or physiological effect. The terms are used in amanner somewhat differently than the terms are typically used in thatwhat is intended by the method of treatment of the invention is to allowa patient to overcome an addiction to nicotine and thereby allow thepatient to quit smoking. The treating effect of the invention provides apsychological effect in that the invention originally delivers highdoses of nicotine in a manner that simulates the nicotine deliveryobtained from a cigarette. The patient then becomes accustomed torelying on the methodology of the invention to provide an immediate“rush” of nicotine. Thereafter, the particles of the aerosol are madelarger. This prevents the particles from penetrating deeply into thelung and, therefore, to some extent, diminishes the “rush” of nicotine.However, the same amount of nicotine is still given to the patient inorder to satisfy the overall nicotine craving. Eventually, the treatmentof the invention reduces the amount of nicotine so as to allow thepatient to completely “wean” off of nicotine and to quit smoking.

[0054] All publications mentioned herein are incorporated herein byreference to described and disclose specific information for which thereference was cited in connection with. The publications discussedherein are provided solely for their stated disclosure prior to thefiling date of the present application. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch publications by virtue of prior invention. Further, the actualpublication date may be different from that stated on the publicationand as such may require independent verification of the actualpublication dates.

General Methodology

[0055] The steady state delivery of nicotine as therapy for smokerswishing to quit is characterized by slow absorption and low blood levelsof nicotine, which limits its utility. The present invention replacesthe nicotine that a smoker receives from smoking a cigarette in atherapeutically effective manner by providing a rapid pulse ofbioavailable nicotine to the smoker on demand.

[0056] One means currently available for a true pulsatile, rapid onsetreplacement therapy is intravenous administration. Although preparationsof nicotine appropriate for intravenous administration have beenavailable for some time, intravenous cannulation as a means for gainingaccess to the circulation for the administration of nicotine on demandis not a socially acceptable alternative to cigarette smoking.

[0057] The treatment methodology of the present invention creates anaerosol of nicotine particles. The nicotine particles may be formed fromany liquid containing nicotine including a solution or suspension ofnicotine and aerosolized in any known manner including (1) moving theformulation through a porous membrane in order to create particles or(2) a dry powder where the particles of powder have been designed tohave a desired diameter. The rate of particle absorption is directlyproportional to the surface area of the tissue on which the particlesare deposited. Accordingly, nicotine is absorbed more slowly through themucosal membranes of the upper respiratory tract which have a smallersurface area than through the airways in the lower respiratory tractwhich have a larger surface area. Thus, the overall effect of increasingthe size of the nicotine particles is to reduce the rate at whichnicotine is absorbed into the circulation, thereby reducing the smoker'sphysiological dependence on the quick rush of nicotine experienced whensmoking.

Method of Treatment

[0058] The penetration of aerosolized nicotine particles into therespiratory tract is determined largely by the size distribution of theparticles formed. Larger particles, i.e., particles with a diameter ≧5μ, deposit on the upper airways of the lungs (see FIG. 1). Particleshaving a diameter in a range of about >2 μ to <5 μ penetrate to thecentral airways. Smaller particles having a diameter ≦2 μ penetrate tothe peripheral region of the lungs.

[0059] An important feature of the invention is that the treatmentmethodology begins with particles of a given size, carries out treatmentfor a given period of time after which the particles are increased insize. The particles initially administered to the patient penetratedeeply into the lung, i.e., the smallest particles (e.g. 0.5 to 2 μ)target the alveolar ducts and the alveoli. When the deepest part of thelung is targeted with the smallest particles the patient receives animmediate “rush” from the nicotine delivered which closely matches thatreceived when smoking a cigarette. These small particles can be obtainedby milling powder into the desired size and inhaling the powder or bycreating a solution or suspension and moving the solution or suspensionthrough the pores of a membrane. In either case, the desired result isto obtain particles which have a diameter in the range of 0.5 μ to about2 μ. Those skilled in the art will understand that some of the particleswill fall above and below the desired range. However, if the majority ofthe particles (50% or more) fall within the desired range then thedesired area of the lung will be correctly targeted.

[0060] The patient is allowed to continually, from time to time, targetthe outermost area of the lung with the smallest particles. For example,the patient would be instructed to repeatedly administer the smallestsize particles when the patient would normally smoke a cigarette. Inthis manner, the patient will become accustomed to finding that thedevice administers nicotine into the patient in the same manner that acigarette does. In one embodiment of the invention the concentration ofthe nicotine in the liquid formulation could be reduced gradually overtime. This could be done over a sufficiently long period of time so asto allow the patient to “wean” off of nicotine. However, in a morepreferred embodiment of the invention the amount of nicotine is keptsubstantially constant but the size of the aerosolized particles createdare increased.

[0061] The second phase of the treatment methodology is to increase thesize of the particles so as to target the respiratory tract above thealveolar ducts and below the small bronchi. This can generally beaccomplished by creating aerosolized particles of nicotine which have asize and range of about 2 μ to about 4 μ. Administration is carried outin the same manner as described above. Specifically, the patientadministers the aerosolized nicotine at the same time when the patientwould be smoking a cigarette. Since the patient has become adjusted toreceiving the nicotine “rush” from the smaller sized particles, thepatient will expect and is therefore likely to experience the same“rush” when administering the slightly larger particles. However, theeffect will be less immediate. This procedure is carried out over aperiod of time, e.g., days or weeks. In one embodiment of the inventionit is possible to reduce the dose of aerosolized nicotine delivered tothe patient during this second phase. However, the dose may remainconstant.

[0062] The treatment can be completed after any phase, e.g. after thesecond phase. However, in accordance with a more preferred embodiment ofthe invention a third phase of treatment is carried out. Within thethird phase the particle size of the aerosolized nicotine is increasedagain. The particles are increased to a size in a range from about 4 μto about 8 μ or, alternatively, perhaps as large as 12 μ. These largerparticles will target the upper airways. The larger particles will givea very small immediate “rush” but will still be absorbed through themucous membranes of the patient's respiratory tract. Accordingly, thepatient will be administering nicotine doses which may be the same asthose doses administered at the beginning of treatment. At this pointthe treatment can take a number of different directions. The patient canattempt to stop administration by immediate and complete cessation ofnicotine delivery. Alternatively, the patient can try to wean off ofnicotine by delivering fewer doses during a given time period. Inanother alternative, the same size dose (volume of aerosol formulation)is administered and delivered, creating the same amount of aerosol, butwherein the aerosolized particles contain progressively less nicotine(i.e., more dilute concentration). The amount of nicotine can bedecreased until the patient is receiving little or no nicotine. Thoseskilled in the art reading this disclosure will recognize variations onthe overall method and methods for stopping treatment.

[0063] There are a number of aspects of the invention which will resultin the ability of the smoker to use the invention and, eventually, quitsmoking. Firstly, the invention is particularly suited for smokers inthat smokers are accustomed to inhaling their source of nicotine. Othertreatments such as those involving the transdermal delivery of nicotinevia a nicotine “patch” or buckle delivery via a nicotine “gum” do notmatch the means which a smoker usually obtains nicotine.

[0064] Further, the present invention provides a method wherein thepatient obtains an influx of nicotine into the circulatory system at arate which substantially matches the rate which nicotine would enter thecirculatory system when smoking. This is obtained because, at least atfirst, the invention provides sufficiently small particles such thatthey are inhaled deeply into the lung, i.e. 50% or more of the particlesare inhaled deeply into the lung and thereby quickly enter the patient'scirculatory system.

[0065] Thirdly, the present invention is advantageous in that the rateat which the delivered nicotine enters the circulatory system can begradually decreased by gradually increasing the size of the aerosolizedparticles delivered to the patient. This can be done over any desiredperiod of time and in any desired number of phases.

[0066] Lastly, the invention provides a means whereby the amount ofnicotine delivered to the patient can be gradually decreased in a numberof different ways. Firstly, it can be decreased by decreasing theconcentration of nicotine in the aerosolized formulation. Secondly, itcan be decreased by merely decreasing the number of administrations ofaerosolized doses. Thirdly, it can be decreased by decreasing the sizeof the dose aerosolized and inhaled by the patient.

[0067] One aspect of the invention is a method of treatment, comprising:

[0068] (a) aerosolizing a formulation comprised of nicotine creatingaerosolized particles which are sufficiently small to target aparticular lower area of the respiratory tract such as the alveoli. Theparticles targeting this area will have a relatively small size, e.g.0.5 micron to about 2 microns in diameter.

[0069] (b) in the next step the patient inhales the aerosolizedparticles of (a) into the respiratory tract, preferably targeted to aspecific area of the lower respiratory tract where the depositedparticles cross into the patient's circulatory system.

[0070] In step (c), steps (a) and (b) are repeated a plurality of times.Specifically, the patient may repeat these steps any number of timessuch as every time the patient would normally smoke a cigarette. At thispoint the patient could continue the treatment protocol in this mannerand gradually decrease the number of times the patient administersaerosolized nicotine until the patient is no longer addicted tonicotine. Decreasing the amount of aerosolized nicotine could also bedone by decreasing the concentration of nicotine within the aerosolizedparticles decreasing the concentration of nicotine in the formulationand/or decreasing the size of the aerosolized dose.

[0071] Preferably the method of the invention continues with a step (d)which involves aerosolizing formulation comprised of nicotine in orderto create aerosolized particles which are larger in size than theaerosolized particles produced in step (a). These larger particles aredirected towards a particular area of the patient's respiratory tract,e.g. the mid-region of the patient's respiratory tract. (See FIGS. 1 and2) These particles could have a size in the range of about 2 microns toabout 4 microns.

[0072] In the following step (d) the patient inhales the aerosolizedparticles of (d) thereby targeting the particular desired area of thepatient's respiratory tract such as the mid region. Thereafter, steps(d) and (e) are repeated a plurality of times. At this point the patientcan decrease the amount of nicotine being delivered as indicated in thesame manner as indicated above step (c). Alternatively, the method ofthe invention can be continued so that a third phase of treatment can becarried out which phase is similar to the two phases described above. Inaccordance with the above invention it is possible to carry out thetreatment in any number of phases. For example, the treatment couldinvolve as many as 24 phases which target specific defined regions of apatients respiratory tract using particles which are continually largerin size in each of the 24 phases (see FIG. 1 and Table 1 below). Becauseit may not be practical to specifically design the particles so thatthey are all larger in each of the phases the formulations may bedesigned so that a certain percentage of the particles within each phaseof delivery is larger than the particles in the preceding phase.

[0073] The method of the invention can be carried out using 1 to 24different phases with each phase targeting a higher level of therespiratory tract (See Table 1). The higher levels of the respiratorytract can be targeted using larger and larger particles. TABLE 1Subdivision of the Respiratory Tree Generation Name  0 Trachea  1Primary bronchi  2 Lobar bronchi  3 Segmental bronchi  4 subsegmentalbronchi  5 Small bronchi ↓ 10 11 Bronchioles, primary and secondary ↓ 1314 Terminal bronchioles ↓ 15 16 Respiratory bronchioles ↓ 18 19 Alveolarducts ↓ 23 24 Alveoli

Nicotine Delivery Devices

[0074] Precision delivery of small molecule drugs via the lung forsystemic effect is possible. An electronic inhaler capable of deliveringa liquid formulated drug stored in a unit dose packages has beendescribed and disclosed in U.S. Pat. No. 5,718,222 entitled “DisposablePackage for Use in Aerosolized Delivery of Drugs,” and is incorporatedherein by reference. A formulation of nicotine can be prepared fordelivery with this system. Quantitative delivery of nicotine on demandprovides a mechanism for nicotine replacement therapy which is unlikelyto be associated with recidivism precipitated by the symptoms ofphysical withdrawal.

[0075] In the present invention, a nicotine formulation is forcedthrough the openings or pores of a porous membrane to create an aerosol.In the preferred embodiment, the openings are all uniform in size andare positioned at uniform distances from each other. However, theopenings can be varied in size and randomly placed on the membrane. Ifthe size of the openings is varied, the size of the particles formedwill also vary. In general, it is preferable to maintain uniform openingsizes in order to create uniform particle sizes, and it is particularlypreferable to have the opening sizes within the range of about 0.25 μ toabout 6 μ which will create particle sizes of about 0.5 μ to 12 μ whichare preferred with respect to inhalation applications. When the openingshave a pore size in the range of 0.25 μ to 1 μ they will produce anaerosol having particle sizes in the range of 0.5 μ to 2 μ, which isparticularly useful for delivering nicotine to the alveolar ducts andalveoli. Pore sizes having a diameter of about 1 μ to 2 μ will produceparticles having a diameter of about 2 μ to 4 μ, which are particularlyuseful for delivering nicotine to the area above the alveolar ducts andbelow the small bronchi. A pore size of 2 μ to 4 μ will create particleshaving a diameter of of 4 μ to 8 μ, which will target the area of therespiratory tract from the small bronchi upward.

[0076] Increasing the size of the openings of the porous membranesproduces nicotine particles of increasing size. A strategy in which theblood level of nicotine is reduced gradually will be the most effectivein treating the symptoms of withdrawal, and thereby increase the chancesof successful smoking cessation. In one embodiment of the invention, thesize of the aerosolized nicotine particles is increased in a stepwisemanner by using porous membranes that create “monodisperse” aerosols,wherein all the particles within the aerosol created have essentiallythe same particle size. Nicotine particles of increasing size areproduced by using membranes of increasing pore sizes.

[0077] In another embodiment, the size of the aerosolized nicotineparticles is increased in gradient fashion by using porous membranesthat create “multi-disperse” aerosols, wherein the particles within theaerosol created have different particle sizes. Membranes which have anincreasing range of pore sizes are used to produce nicotine particles ofincreasing size.

[0078] Nicotine can be administered orally. However, after oraladministration it is absorbed from the gut into the portal blood anddegraded promptly by the liver. Thus, insignificant amounts reach thepatient's systemic circulation. Nicotine can also be administeredparenterally. However, when so administered it is rapidly absorbed andmetabolized making it difficult to sustain therapeutic levels in plasmaover time. In view of such, effective therapy has been carried out usingother means of delivery (e.g., transdermal patches, gum). The presentinvention uses intrapulmonary delivery to avoid first pass livermetabolism and to obtain quick infusion into the patient's systemiccirculatory system. The present invention administers sufficientnicotine by inhalation to temporarily produce a rapid increase in thepatient's blood level, and thereafter allow the patient's nicotine levelto return to a therapeutically effective level.

[0079] Because intrapulmonary administration is not 100% efficient, theamount of drug aerosolized will be greater than the amount that actuallyreaches the patient's circulation. For example, if the inhalation systemused is only 50% efficient then the patient will aerosolize a dose whichis twice that needed to raise the patient's nicotine level to the extentneeded to obtain the desired results. More specifically, when attemptingto administer 1 mg of nicotine with a delivery system known to be 50%efficient, the patient will aerosolize an amount of formulationcontaining about 2 mg of nicotine.

[0080] A device comprised of a container that includes an openingcovered by a porous membrane, such as the device disclosed in U.S. Pat.No. 5,906,202, may be used to deliver nicotine. The device may bedesigned to have the shape and/or bear the markings of a pack ofcigarettes, and may include the scent of tobacco. These features andothers that address the behavioral component of cigarette smoking mayenhance the effectiveness of the method described herein.

Dosing

[0081] Cigarettes contain 6 to 11 mg of nicotine, of which the smokertypically absorbs 1-3 mg; see Henningfield N Engl J Med 333:1196-1203(1995). Factors influencing nicotine absorption includesubject-dependent factors, such as smoking behavior, lung clearancerate, etc., morphological factors, and physiological factors, such astidal volume, inspiratory and expiratory flow rate, particle size anddensity. See Darby et al., Clin Pharmacokinet 9:435-439 (1984). Thesystemic dose of nicotine per puff is extremely variable, however, peakplasma concentrations of 25-40 ng/mL of nicotine, achieved within 5-7minutes by cigarette smoking, are believed typical. In accordance withthe present invention, 0.1 mg to 10 mg, preferably 1 to 3 mg, and morepreferably about 2 mg of nicotine are delivered to the lungs of thepatient in a single dose to achieve peak blood plasma concentrations of15-40 ng/mL.

[0082] The amount of a nicotine administered will vary based on factorssuch as the age, weight and frequency of smoking or nicotine toleranceof the smoker. Other factors, such as daily stress patterns, demographicfactors may also determine, in part, the amount of nicotine sufficientto satisfy the smoker's craving for nicotine. Administering nicotineusing the methods of the present invention can involve the dailyadministration of anywhere from 5 mg to 200 mg of nicotine, but morepreferably involves the administration of approximately 10 to 100 mg perday.

[0083] It is noted that nicotine can be administered in toxic amounts.Care should be taken not to overdose the patient. The amount of nicotinewhich an individual can tolerate will vary on a number of factorsincluding size, sex, weight and amount of cigarette smoking the patientis accustomed to. In order to avoid overdosing it is possible to programa lock-out system into the delivery device which prevents administrationof acrosolized doses beyond a given point. Such a system is describedwithin U.S. Pat. No. 5,735,263 issued Apr. 7, 1998 and incorporatedherein by reference in its entirety to disclose drug delivery devicesand lock-out systems used in connection therewith.

[0084] The nicotine is in a liquid form or is dissolved or dispersedwithin a pharmaceutically acceptable, liquid excipient material toprovide a liquid, flowable formulation which can be readily aerosolized.The container will include the formulation having nicotine therein in anamount of about 10 mL to 300 mL, more preferably about 200 mL. The largevariation in the amounts which might be delivered is due to differentdelivery efficiencies for different devices. Administration may involveseveral inhalations by the patient, with each inhalation providingnicotine from the device. For example, the device can be programmed soas to release the contents of a single container or to move from onecontainer to the next on a package of interconnected containers.Delivering smaller amounts from several containers can have advantages.Since only small amounts are delivered from each container and with eachinhalation, even a complete failure to deliver nicotine with a giveninhalation is not of great significance and will not seriously disturbthe reproducibility of the dosing event. Further, since relatively smallamounts are delivered with each inhalation, the patient can safelyadminister a few additional micrograms (or milligrams) of nicotinewithout fear of overdosing.

[0085] In one embodiment of the invention the patient is treated in thethree different phases. In the first phase the aerosolized liquidparticles or dry powder particles have a size and a range of 0.5 μ toabout 2 μ. The particles of nicotine having this size are administeredin a dosage amount which is substantially equivalent to the doses oramount which the patient would received from a single cigarette or,alternatively, the dosage amount which the patient would received from asingle puff on a single cigarette. Assuming that the patient receivesthe dosage amount of a single cigarette then the patient will beadministered approximately 1 to 3 mg of nicotine each time theformulation is aerosolized. The particles having a size of 0.5 μ toabout 2 μ will be administered to the patient over a plurality of days(e.g., 2 to 7 days) or perhaps a plurality of weeks (e.g., 2 to 4weeks). If the device and/or dosage containers are designed to deliver adosage equivalent to a puff on a cigarette then substantially smallerdoses are delivered. If each dose corresponds to a puff on a cigarettethen a patient may be directed to continually take aerosolized dosesequivalent to a cigarette puff over a period of one to ten minutes orany period of time equivalent to what that patient normally takes tosmoke one cigarette. This constitutes the first phase of treatment.

[0086] After completing the first phase of the treatment the method ofthe invention may be completed. However, as indicated above the methodmay be continued by repeating phases such as the first phase usingcontinually larger particles and/or continuing more dilute solutions ofnicotine and/or smaller doses of nicotine.

[0087] Within the second phase of treatment the patient is preferablyadministered the same dosage amount of nicotine with each inhalation,e.g., the patient is administered 1 to 3 mg of nicotine each timeformulation is aerosolized. However, during the second phase the size ofthe particles is increased to a size and range from 2 μ to about 4 μ.The particle size is increased in order to target an area of the lungswhere the nicotine will be absorbed into the circulatory system moreslowly. Specifically, the larger particles target an area of the lungsabove the alveolar ducts and below the small bronchi. Administration iscarried out over a plurality of days or a plurality of weeks in the samemanner as indicated above. Within all phases the patient preferablyadministers nicotine from a device of the invention when the patientwould normally smoke a cigarette. The treatment can be completedpursuant to the present invention by using only the two phases. However,it is preferable to include three or more phases.

[0088] In accordance with the third phase, the same dose is administeredeach time nicotine formulation is aerosolized. Accordingly, 1 to 3 mg ofnicotine is delivered to the patient at each dose. However, the dose isdelivered by using aerosolized particles which have a diameter of 4 μ ormore, e.g., in the range of from 4 μ to about 8 μ. These largerparticles are designed to target the area of the respiratory tract atthe small bronchi or higher. When the nicotine targets the upper airwaysit will not immediately enter the patient's circulatory system. However,the nicotine will, eventually, cross the mucous membranes of the upperrespiratory tract and enter the circulatory system. Thus the patientwill be administered nicotine but will become less accustomed to havingthe immediate “rush” obtained from smoking. Thus, within the third phasethe patient has been weaned away from the need for the “rush” ofnicotine. The third phase is then used to continually reduce the numberof administrations needed and thereby reduce the amount of nicotineadministered. By this process the patient's dependency on nicotine isslowly reduced and then eliminated thereby allowing the patient to quitsmoking.

[0089] When nicotine enters the circulatory system of a human patient itis oxidized to cotinine within four to six hours. The present inventionincludes the administration of cotinine and other nicotine derivativesprovided such derivatives do not result in unacceptable adverse effects.

Indications

[0090] The method of the invention has applicability to smokers wishingto quit or trying to quit who have experienced all or any of thenicotine withdrawal symptoms associated with smoking cessation, such ascraving for nicotine, irritability, mood ability, frustration or anger,anxiety, drowsiness, sleep disturbances, impaired concentration,nervousness, restlessness, decreased heart rate, increased appetite andweight gain.

[0091] While particularly applicable to smoking cessation, pulmonaryadministration of nicotine could be of value for the treatment of otherdiseases, such as for patients suffering from neurodegenerativediseases, psychiatric disorders and other central nervous systemdisorders responsive to nicotinic receptor modulation (see U.S. Pat.Nos. 5,187,169; 5,227,391; 5,272,155; 5,276,043; 5,278,176; 5,691,365;5,885,998; 5,889,029; 5,914,328). Such diseases include, but are notlimited to, senile dementia of the Alzheimer's type, Parkinson'sdisease, schizophrenia, obsessive-compulsive behavior, Tourette'sSyndrome, depression, attention deficit disorder, myasthenia gravis anddrug addiction.

Formulations

[0092] Pharmaceutical grade nicotine can be produced as a colorless topale yellow liquid. The pure liquid could be aerosolized and inhaled byitself. Alternatively, a formulation may include a buffer to enhanceabsorption. Any absorption enhancers including ammonia could be usedwith the formulation. However, a typical formulation is only nicotinedissolved in water or dry powder nicotine. Methods of formulatingliquids and liquid inhalers are disclosed in U.S. Pat. Nos. 5,364,838;5,709,202; 5,497,763; 5,544,646; 5,718,222; 5,660,166; 5,823,178; and5,910,301; all of which are incorporated by reference to describe anddisclose such. Formulations of nicotine include aqueous formulations,aqueous saline formulations, and ethanol formulations. All of theseformulations may be included with additional components such aspermeation enhancers, buffers, preservatives and excipient and carriercomponents and additives normally included within formulations foraerosolized drug delivery.

[0093] Nicotine is freely soluble in water. An aqueous nicotine solutionmay be readily aerosolized and inhaled. The nicotine solution can beplaced in a low boiling point propellant in a pressurized canister andreleased using a conventional metered dose inhaler (MDI) device.Preferably, the MDI device is modified so that the aerosolized dose isreleased each time at the same inspiratory flow rate and inspiratoryvolume. When this is done the patient is more likely to receive the samedose each time. A device for obtaining repeating dosing with an MDIcanister is taught in U.S. Pat. No. 5,404,871.

[0094] In accordance with the present invention it is preferable to loadthe nicotine solution into a container which opens to a porous membrane.When the formulation is forced through the membrane it is aerosolized.Such a container is taught in U.S. Pat. No. 5,497,763 and is loaded intoa device and delivered via a method as taught in U.S. Pat. No.5,823,178. Both patents are incorporated herein by reference to describeand disclose containers, devices and methods of drug delivery byinhalation.

[0095] A dry powder formulation comprising a pharmacologicallyacceptable salt of nicotine alone or with additives such as componentsto prevent the particles from sticking together may be used.

Supplemental Treatment Methodology

[0096] Smokers wishing to quit may be treated solely with respiratorynicotine as indicated above, i.e. by intrapulmonary delivery. However,it is possible to treat such patients with a combination of pulmonaryadministration and other means of administration, such as transdermaladministration. Transdermal nicotine is preferably administered tomaintain a steady state level of nicotine within the circulatory system.Nasal or buccal formulation could be used for nasal or buccal deliverywhich could supplement aerosolized delivery.

[0097] Based on the above, it will be understood by those skilled in theart that a plurality of different treatments and means of administrationcan be used to treat a single patient. For example, a patient can besimultaneously treated with nicotine by transdermal administration,nicotine via pulmonary administration, in accordance with the presentinvention, and nicotine which is administered to the mucosa.

[0098] The instant invention is shown and described herein in a mannerwhich is considered to be the most practical and preferred embodiments.It is recognized, however, that departures may be made therefrom whichare within the scope of the invention and that obvious modificationswill occur to one skilled in the art upon reading this disclosure.

What is claimed is:
 1. A system for aiding a patient in quittingsmoking, comprising: a device for aerosolizing a formulation; a firstplurality of containers which are designed for being loaded into thedevice for aerosolizing formulation wherein the containers are comprisedof nicotine and a pharmaceutically acceptable carrier and wherein thenicotine is present in a first concentration; a second plurality ofcontainers capable of being loaded into the device for aerosolizingformulation wherein the formulation in the second plurality ofcontainers is comprised of nicotine and a pharmaceutically acceptablecarrier and further wherein the nicotine is present in the formulationin a second concentration which is less than the first concentration. 2.The system of claim 1, further comprising: a third plurality ofcontainers which are designed for being loaded into the device foraerosolizing formulation wherein the containers are comprised ofnicotine and a pharmaceutically acceptable carrier and wherein thenicotine is present in a third concentration which is less than thesecond concentration.
 3. The system as claimed in claim 1, wherein theformulation in the first plurality of containers and the formulation inthe second plurality of containers is a liquid flowable formulationwherein the nicotine is present in the formulation in a solution orsuspension.
 4. The system as claimed in claim 3, wherein the firstplurality of containers comprises a porous membrane for each containerand further wherein the second plurality of containers comprises aporous membrane for each container.
 5. The system as claimed in claim 1,wherein the formulation in the first plurality of containers and theformulation in the second plurality of containers is a dry powderformulation.
 6. The system as claimed in claim 1, wherein the firstplurality of containers comprises two or more canisters which canisterscontain the formulation in the form of nicotine and low boiling pointpropellant and wherein the second plurality of containers comprises twoor more canisters wherein the formulation in the canisters comprisesnicotine and a low boiling point propellant.
 7. The system as claimed inclaim 1, wherein the device for aerosolizing formulation is a hand-held,self-contained device.
 8. The system as claimed in claim 1, wherein thefirst plurality of containers each comprise a porous membrane whereinthe pores have a first average size, and wherein the second plurality ofcontainers each comprise a porous membrane wherein the pores have asecond average size which is larger than the first average size of thepores in the membrane of the first plurality of containers.
 9. A devicefor aerosolizing a nicotine formulation, comprising: a means foraerosolizing formulation by applying force; and a means for adjustingthe means for aerosolizing formulation so that a different amount offorce can be applied based on the adjustment.
 10. The device as claimedin claim 9, further comprising: a container loaded into the device whichcontainer is comprised of a formulation comprised of nicotine and apharmaceutically acceptable carrier.
 11. A kit for aiding a patient inquitting smoking, comprising: a first plurality of containers havingtherein nicotine and a pharmaceutically acceptable carrier, wherein thenicotine is present in a first concentration; a second plurality ofcontainers having therein nicotine and a pharmaceutically acceptablecarrier wherein the nicotine is present in a second concentration whichis less than the first concentration.
 12. The kit as claimed in claim11, wherein the first plurality of containers and second plurality ofcontainers hold the nicotine and pharmaceutically acceptable carrier ina liquid flowable form.
 13. The kit as claimed in claim 11, wherein thefirst plurality of containers and second plurality of containers eachhold the nicotine and pharmaceutically acceptable carrier in a drypowder form.
 14. A method of treatment, comprising: (a) aerosolizing aformulation comprised of nicotine creating aerosolized particles whichare sufficiently small as to target the alveoli of a patient'srespiratory tract; (b) allowing the patient to inhale the aerosolizedparticles of (a) thereby causing nicotine to enter the patient's blood;(c) repeating (a) and (b) a plurality of times; (d) aerosolizing aformulation comprised of nicotine creating aerosolized particles whichare sized in order to target the bronchioles of the patient'srespiratory tract; (e) allowing the patient to inhale the aerosolizedparticles of (d) thereby targeting the bronchioles of the respiratorytract; and (f) repeating (d) and (e) a plurality of times.
 15. Themethod of claim 14, further comprising: (g) aerosolizing a formulationcomprised of nicotine creating aerosolized particles which are sized inorder to target the bronchi of the patient's respiratory tract; (h)allowing the patient to inhale the aerosolized particles of (g) into thebronchi of the respiratory tract; and (i) repeating (g) and (h) aplurality of times.
 16. The method of claim 14, wherein the formulationis a liquid formulation comprising nicotine and an excipient selectedfrom the group consisting of an aqueous solvent to form solutions and aliquid to form suspensions.
 17. The method of claim 14, wherein theformulation comprises a solution or suspension of a nicotine and anaqueous solvent or liquid carrier and the aerosolized particles arecreated by moving the formulation through a porous membrane.
 18. Amethod of treatment, comprising: (a) aerosolizing a formulationcomprising about 0.25 mg or more of nicotine to create aerosolizedparticles which target an area of a patient's respiratory tract; (b)allowing the patient to inhale the aerosolized particles of (a) therebycausing nicotine to enter the patient's blood; (c) repeating (a) and (b)a plurality of times.
 19. The method of claim 18, further comprising:(d) aerosolizing a formulation comprising about 0.25 mg or more ofnicotine to create aerosolized particles which target a second area ofthe patient's respiratory tract; (e) allowing the patient to inhale theaerosolized particles of (d) to the second area of the patient'srespiratory tract; and (f) repeating (d) and (e) a plurality of times.20. A method comprising the steps of: (a) aerosolizing a formulationcomprised of nicotine creating aerosolized particles having a diameterof 0.5 μ to about 2 μ; (b) allowing the patient to inhale theaerosolized particles of (a) into the patient's respiratory tract; (c)repeating (a) and (b) a plurality of times; (d) aerosolizing aformulation comprised of nicotine creating aerosolized particles havinga diameter of 2 μ to about 4 μ; (e) allowing the patient to inhale theaerosolized particles of (d) into the patient's respiratory tract; and(f) repeating (d) and (e) a plurality of times.
 21. The method of claim20, further comprising the steps of: (g) aerosolizing a formulationcomprised of nicotine creating aerosolized particles having a diameterof 4 μ to about 8 μ; (h) allowing the patient to inhale the aerosolizedparticles of (g) into the patient's respiratory tract; and (i) repeating(g) and (h) a plurality of times.